Rahmanzadeh, RezaLu, Po-JuiBarakovic, MuhamedWeigel, MatthiasMaggi, PietroNguyen, Thanh D.Schiavi, SimonaDaducci, AlessandroLa Rosa, FrancescoSchaedelin, SabineAbsinta, MartinaReich, Daniel S.Sati, PascalWang, YiCuadra, Meritxell BachRadue, Ernst-WilhelmKuhle, JensKappos, LudwigGranziera, Cristina2021-11-202021-11-202021-11-202021-06-0110.1093/brain/awab088https://infoscience.epfl.ch/handle/20.500.14299/183160WOS:000710929200017Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging.We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study.Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy control subjects and normal-appearing multiple sclerosis tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P < 0.0001) and peri-plaque white matter (P < 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region ( P < 0.0001 and P < 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P < 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P < 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normalappearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P < 0.01, beta = -10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort (P < 0.01, beta = -3.60 and P < 0.01, beta = 0.13, respectively).These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting patients because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.Clinical NeurologyNeurosciencesNeurosciences & Neurologymultiple sclerosismyelin water imagingdiffusion microstructural modellingneurodegenerationdemyelinationnormal-appearing whitemagnetization-transfer rationeurite orientation dispersiongray-matterlesionsdiseaseremyelinationdisabilityinjurytext::journal::journal article::research article